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Aniline-based wdr5 protein-protein interaction inhibitor, and preparation method and use thereof

Pending Publication Date: 2022-05-19
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent is about a chemical compound that can inhibit the activity of a protein called WDR5, which is involved in the development of hematological tumors like leukemia. The compound can also reduce the expression of certain genes involved in tumor growth. This makes it a potentially effective treatment for these types of cancers.

Problems solved by technology

Conventional chemotherapy for the treatment of leukemia caused by MLL abnormality is undesirable with poor prognosis.

Method used

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  • Aniline-based wdr5 protein-protein interaction inhibitor, and preparation method and use thereof
  • Aniline-based wdr5 protein-protein interaction inhibitor, and preparation method and use thereof
  • Aniline-based wdr5 protein-protein interaction inhibitor, and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0027]

N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)quinazoline-4-amine

Step 1: Preparation of 2-(4-methylpiperazin-1-yl)-5-nitrophenylamine

[0028]2-fluoro-5-nitrophenylamine (2 g, 12.8 mmol) was dissolved in DMF (20 mL), and then DIPEA (3.3 g, 25.6 mmol) and 1-methylpiperazine (25.6 mmol) were added. The mixture was stirred at 100° C. for 8 hrs. 100 mL of water was added to the reaction mixture, which was extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and distilled under reduced pressure, to obtain a crude product, which was washed with CH3CN to obtain a yellow solid. Yield 53.0%; m.p. 200° C.-202° C. 1H NMR (300 MHz, DMSO-d6) δ 7.53 (d, J=2.4 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.04 (d, J=8.7 Hz, 1H), 5.26 (s, 2H), 3.11 (s, 4H), 2.58 (s, 4H), 2.24 (s, 3H). HRMS (ESI): calcd. for m / z C11H17N4O2, [M+H]+ 237.1316, found 237.1342.

Step 2: Preparation of Titled Compound

[0029]N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)quinazoline-4-...

example 2

[0030]

6-chloro-N-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)pyrimidine-4-amine

[0031]Following the method in Step 2 of Example 1, 4-chloroquinazoline was replaced by 4, 6-dichloropyrimidine (1.69 mmol), to obtain a yellow solid. Yield 65.8%; m.p. 169° C.-171° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.48 (s, 1H), 8.42 (d, J=2.7 Hz, 1H), 8.02 (dd, J=8.9, 2.8 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 6.81 (s, 1H), 3.04 (t, J=4.6 Hz, 4H), 2.35 (t, J=4.7 Hz, 4H), 2.16 (s, 3H). HRMS (ESI): calcd. for m / z C15H17ClN6O2, [M+H]+ 349.1174, found 349.1177. HPLC (100% MeOH): tR=6.097 min, 96.84%.

example 3

[0032]

N4, N4-dimethyl-N6-(2-(4-methylpiperazin-1-yl)-5-nitrophenyl)pyrimidine-4,6-diamine

[0033]The title compound of Example 2 (0.35 mmol) was dissolved in DMF (5 mL), and then DIPEA (1.5 mmol) and dimethylamine (1 mmol) were added. The mixture was kept at 120° C. for 4 hrs. The reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL×3), and then washed with a saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered under suction, and spin-dried. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain a yellow solid. Yield 49.5%; m.p. 152° C.-154° C.; 1H NMR (300 MHz, CDCl3) δ 8.69 (d, J=2.7 Hz, 1H), 8.28 (s, 1H), 7.80 (dd, J=8.7, 2.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.94 (s, 1H), 5.82 (s, 1H), 3.03 (s, 6H), 2.94 (t, J=4.8 Hz, 4H), 2.65-2.48 (m, 4H), 2.30 (s, 3H). HRMS (ESI): calcd. for m / z C17H23N7O2, [M+H]+ 358.1986, found 358.1992. HPLC (100% MeOH): tR=4.7...

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Abstract

The present disclosure discloses a WDR5 protein-protein interaction inhibitor, including a compound having a structure represented by general formula (I). Experiments show that the inhibitor acts on a WDR5 protein and an interacting protein thereof including, but not limited to, MLL, selectively inhibits the proliferation of leukemia cells, and inhibits the methylation of H3K4 and the expression of downstream Hox / Meis-1 gene at the cellular level. The present disclosure also discloses a method for preparing the inhibitor and use thereof in the preparation of a drug for treating acute leukemia and other related diseases.

Description

TECHNICAL FIELD[0001]The present disclosure relates to an aniline compound in medicinal chemistry, a preparation method thereof, and use thereof. As a WDR5 protein-protein interaction inhibitor, the compound inhibits the level of a histone methyltransferase and the expression of a downstream hematopoietic gene at the cellular level, inhibits the growth of transplanted tumors in nude mice at the animal level, and can be used to treat diseases such as acute leukemia.BACKGROUND[0002]A WDR5 protein includes 334 amino acids, and contains 7 WD40 repeat domains. Structural studies have shown that the WD40 repeat domains form a 7-blade propeller structure, each blade including 4 antiparallel chains. Such a structural feature enables WDR5 to interact with many other proteins, for example, WDR5-MLL1, WDR5-MYC, and WDR5-MOF / HAT. WDR5 may also bind to H3K4me2. Studies have shown that the WDR5 may stabilize or assemble a VISA (virus-induced signaling adaptor)-related complex, and plays an import...

Claims

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Application Information

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IPC IPC(8): A61K31/517A61P35/00A61K31/506A61K31/5355
CPCA61K31/517A61K31/5355A61K31/506A61P35/00A61P35/02C07D239/94C07D401/12C07D403/12C07D405/12C07D239/42C07D239/48C07D213/74C07D239/47A61K31/5377C07D239/95
Inventor YOU, QI DONGGUO, XIAOKECHEN, WEILINLI, DONGDONGGU, JINGXU, JUNCHEN, XINJIANG, ZHENGYUXU, XIAOLI
Owner CHINA PHARM UNIV
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